PROJECT SUMMARY/ABSTRACT Margaret Salisbury, MD, MS is a Pulmonary and Critical Care physician at the University of Michigan. This K23 mentored career development application includes a coordinated 5-year plan of training and research activities designed to advance Dr. Salisbury toward her long-term goal of becoming an independent physician-scientist and leader in interstitial lung disease (ILD) patient-oriented research, with a focus on phenotyping and treatment of hypersensitivity pneumonia (HP). ILD affects up to 1 in 14 American adults, with HP prevalent among these. HP results from immune system activation following antigen inhalation, and is heterogeneous in terms of clinical presentation and disease biology. The fibrotic form is associated with poor survival and a comparable course to idiopathic pulmonary fibrosis (IPF). The host immunologic response and microbes present in the lungs (the ?lung microbiome?) likely influence ILD outcomes. Understanding how these biologic variables relate to fibrosis and disease progression represents a key step toward developing effective, personalized treatments for patients with HP, thereby improving the prognosis of this life-threatening disease. The specific Aims of this project are to: 1) Identify differences across ILD diagnosis groups in the host immune response and lung microbiome composition at the time of diagnosis; and 2) Identify key host immune response and lung microbiome markers that predict lung function change in HP and IPF populations. To complete these aims, Dr. Salisbury will conduct a prospective cohort study of ILD patients undergoing diagnostic lung sampling procedures, with host response and lung microbiome markers measured in concurrently-collected bronchoalveolar lavage fluid. Identified HP and IPF patients will undergo serial pulmonary function measurement in the year following the diagnostic procedure. Mixed effects models will identify baseline host response and microbiome variables independently predictive of pulmonary function trajectory. In completion of this project, Dr. Salisbury will gain experience in the study of lung immunology, microbial ecology, and clinical research methods. These skills will complement her existing expertise in clinical care of patients with ILDs, and already-completed didactic training in clinical research methods. The training plan includes intensive mentorship by experts in clinical trials (Kevin Flaherty, MD MS, primary mentor), lung immunology (Bethany Moore, PhD), microbial ecology (Gary Huffnagle, PhD), and biostatistics (Susan Murray, ScD), select coursework, and participation in a scientific community. Completion of this progressively independent research project will lead to study of therapeutic manipulation of the host immune response and/or lung microbiome in subsequent R01, U01, and/or R21 applications. Dr. Salisbury's unique resources include access to a dedicated mentorship team with whom she has long-standing collaborations. The University of Michigan has an outstanding research infrastructure, actively supports junior investigators, and offers advanced courses in relevant disciplines.